While cumulative morbidity and mortality of cancers keep rising, early discovery of cancers at any parts is a problem that needs to be solved. Early discovery not only can reduce invasion upon a treatment but also a complete cure can be expected. For patients who have already been diagnosed with progressive cancer, accurate diagnosis of the presence of a distant metastasis is very important for determining the disease stage and for determining the subsequent therapeutic strategy. Examples of a treatment of a cancer include surgical treatment, radiation therapy and chemotherapy, where the surgical treatment can be expected to radically cure the cancer by accurately resecting or ablating the metastatic focus upon the treatment. Also in the case of the radiation therapy, side effects can be alleviated by precisely determining the site of tumor to focus the irradiation and prevent irradiation of a healthy site. In this regard, for any patient at any stage, it is a great advantage to perform correct diagnosis of the cancer site, especially correct diagnosis of the highly malignant cancer.
Typical examples of diagnostic imaging methods for malignant tumors include X-ray computed tomography (CT), ultrasound and magnetic resonance imaging (MRI). These examinations are highly popularized and each has both advantages and disadvantages. Among them, MRI is the most rapidly prevailing diagnostic imaging technology, which importance is particularly increasing recently because it has no problem of radiation exposure or the like, it is capable of visualizing qualitative changes of a soft tissue and it has high objectivity and reproducibility. MRI, however, has difficulty in identifying small tumors because signals of the small tumors are buried in complicated signals of normal tissues only with its hardware. Therefore, in order to enhance the diagnostic accuracy, development of an MRI contrast agent that is capable of selectively extracting a tumor tissue has been a great issue.
Until now, various imaging agents have been developed and put into practical use for increasing the contrast between a tumor tissue and its surrounding tissue. Typical examples of such contrast agents include metal complexes such as Gd-DTPA (gadolinium-diethylenetriamine-pentaacetic acid) (for example, Non-patent Document 1: Wesbey G E, et al. Physiol Chem Phys Med NMR. 1984; 16(2):145-155). Gd-DTPA, however, lacks site specificity, and thus has no targeting property to a specific tissue such as a cancer and rapidly diffuses to respective organs and muscles upon transveous administration. Therefore, it has difficulty in making a definitive diagnosis of a tumor. Gd-DTPA has less side effects through chelation compared to free Gd ion but the dosage and the concentration (500 mM as an undiluted solution) are great. For example, if blood retention in a patient with renal damage or the like is prolonged, Gd is ionized and may pose a risk for causing a serious symptom called nephrogenic systemic fibrosis. Meanwhile, an Mn ion is a contrast agent that enhances contrast for MRI, like Gd-DTPA and else, but if it is transvenously administered alone at the same concentration of Gd-DTPA, serious side effects such as cardiac toxicity are caused. On the other hand, Mn is one of living body essential elements, which does not cause toxicity even when retained in the body in a very small amount and is clinically approved as an oral contrast agent.
Recently, in the field of diagnostic imaging, development of smart function-type probes that are not only capable of simply visualizing a cancer tissue but also capable of depicting the property and the state of the cancer such as the grade of malignancy and cell death has been increasing (for example, Non-patent Document 2: Urano et al., Nat Med. 2009 January; 15(1):104-109). Most of them, however, are fluorescent probes, and there is almost no practical studies regarding MRI contrast agents.